Alternative titles; symbols
HGNC Approved Gene Symbol: TUBB4B
Cytogenetic location: 9q34.3 Genomic coordinates (GRCh38): 9:137,241,287-137,243,707 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q34.3 | Leber congenital amaurosis with early-onset deafness | 617879 | Autosomal dominant | 3 |
Microtubules are dynamic polymeric structures consisting of heterodimers of alpha-tubulins (see 602529) and beta-tubulins, such as TUBB4B, that are continuously incorporated and released. Microtubules function in mitosis, intracellular transport, neuron morphology, and ciliary and flagellar motility (Leandro-Garcia et al., 2010).
Lewis et al. (1985) cloned the tubulin beta-2 isoform gene. The beta-2 gene is expressed as a 1.8-kb mRNA, and the sequence encodes a predicted 445-amino acid protein. Lewis and Cowan (1990) stated that the mouse homolog of beta-2, M-beta-3, is expressed abundantly in testis and at lower levels in many other tissues.
Using database analysis, Leandro-Garcia et al. (2010) identified 8 major beta-tubulins, including TUBB4B, which they called TUBB2C. Quantitative RT-PCR showed variable TUBB2C expression in all 21 normal human tissues examined, with highest expression in heart and testis, and lowest expression in prostate. TUBB2C was the predominant beta-tubulin isotype in testis, kidney, heart, skeletal muscle, and lung. Abnormal TUBB2C expression was detected in several tumors compared with their normal counterparts.
Luscan et al. (2017) studied a spectrum of mouse tissues and observed expression of Tubb4b mRNA in all analyzed embryonic and adult tissues, including retina and cochlea, with significantly higher expression in the retina compared to the other tissues.
Lewis and Cowan (1990) reviewed the beta-tubulin gene family. In humans, this family consists of 15 to 20 dispersed genes, many of which are processed pseudogenes. The positions of the first 2 introns are identical among members of the human and chicken gene families. Within a vertebrate species, the genes are distinguished by their C-terminal region. The amino acid sequence differences show varying degrees of conservation across species, depending on the isotype.
Hartz (2013) mapped the TUBB4B gene to chromosome 9q34.3 based on an alignment of the TUBB4B sequence (GenBank BC001911) with the genomic sequence (GRCh37).
In 5 affected individuals from 4 families with Leber congenital amaurosis and early-onset deafness (LCAEOD; 617879), Luscan et al. (2017) identified heterozygosity for missense mutations in the TUBB4B gene: R391H (602660.0001) in 3 families, and R391C (602660.0002) in the remaining family. Functional analysis demonstrated that the mutations have a significant dampening impact on microtubular growth.
In 4 patients from 3 families with Leber congenital amaurosis and early-onset deafness (LCAEOD; 617879), including an affected mother and son (family 1), Luscan et al. (2017) identified heterozygosity for a c.1172G-A transition (c.1172G-A, NM_006088.5) in the TUBB4B gene, resulting in an arg391-to-his (R391H) substitution at a residue within a binding pocket that interacts with alpha-tubulin. In a 6-year-old French girl (family 3), the mutation was shown to have arisen de novo, not being present in her unaffected parents or an unaffected sister. In the remaining 2 families, the R391H variant was inherited from a mosaic parent. In family 1, the mildly affected maternal grandmother was mosaic for the mutation, which was present in only 29% of reads and had arisen de novo. In family 2, a 31-year-old affected Algerian man inherited the mutation from his unaffected mosaic father, in whom the variant was present in only 13% of reads. Experiments with transfected COS-7 cells showed that the R391H mutant was able to fold, form alpha-beta dimers, and coassemble into the endogenous microtubule lattice. However, the mutant had a significant impact on microtubule repolarization dynamics, causing depressed microtubule growth rates compared to wildtype. Analysis of patient fibroblasts confirmed dramatically diminished microtubule growth rates.
In a 9-year-old Danish boy with Leber congenital amaurosis and early-onset deafness (LCAEOD; 617879), Luscan et al. (2017) identified heterozygosity for a de novo c.1171C-T transition (c.1171C-T, NM_006088.5) in the TUBB4B gene, resulting in an arg391-to-cys (R391C) substitution at a residue within a binding pocket that interacts with alpha-tubulin. The mutation was not found in his unaffected parents or 2 unaffected sisters. Experiments with transfected COS-7 cells showed that the R391C mutant was able to fold, form alpha-beta dimers, and coassemble into the endogenous microtubule lattice. However, the mutant had a significant impact on microtubule repolarization dynamics, causing depressed microtubule growth rates compared to wildtype. Analysis of patient fibroblasts confirmed dramatically diminished microtubule growth rates.
Hartz, P. A. Personal Communication. Baltimore, Md. 2/28/2013.
Leandro-Garcia, L. J., Leskela, S., Landa, I., Montero-Conde, C., Lopez-Jimenez, E., Leton, R., Cascon, A., Robledo, M., Rodriguez-Antona, C. Tumoral and tissue-specific expression of the major human beta-tubulin isotypes. Cytoskeleton 67: 214-223, 2010. [PubMed: 20191564] [Full Text: https://doi.org/10.1002/cm.20436]
Lewis, S. A., Cowan, N. J. Tubulin genes: structure, expression, and regulation.In: Avila, J. (ed.) : Microtubule proteins. Boca Raton: CRC Press, Inc. 1990. Pp. 37-66.
Lewis, S. A., Gilmartin, M. E., Hall, J. L., Cowan, N. J. Three expressed sequences within the human beta-tubulin multigene family each define a distinct isotype. J. Molec. Biol. 182: 11-20, 1985. [PubMed: 3999141] [Full Text: https://doi.org/10.1016/0022-2836(85)90023-3]
Luscan, R., Mechaussier, S., Paul, A., Tian, G., Gerard, X., Defoort-Dellhemmes, S., Loundon, N., Audo, I., Bonnin, S., LeGargasson, J.-F., Dumont, J., Goudin, N., and 12 others. Mutations in TUBB4B cause a distinctive sensorineural disease. Am. J. Hum. Genet. 101: 1006-1012, 2017. [PubMed: 29198720] [Full Text: https://doi.org/10.1016/j.ajhg.2017.10.010]